L-Gulose was first prepared by Emil Fischer in 1888. [Fischer, et al, Ber. 24, 526 (1888)] During the past 100 years, many other syntheses of L-gulose have been reported, including the following: Ko, et al, Science, 220 (4600), 949-51 (1983); U.S. Pat. No. 4,371,616, Huibers, issued Feb. 1, 1983; German Offen. DE 32 28 898 A1, Huibers, issued Mar. 10, 1983; U.S. Pat. No. 4,262,032, Levin, issued Apr. 14, 1981; Evans, et al, Methods of Carbohydr. Chem. 8, 173-6 (1980); Dahlhoff, et al, Agnew. Chem., 92(7) 552-3 (1980); Evans, et al, Carbohyd. Res., 28(2), 359-64 (1973); and Sowden, et al., J. Am. Chem. Soc., 67, 1713-1715 (1945).
L-Gulose has recently been found to have value as a non-caloric or reduced caloric sweetener. It has been found that L-hexose have sweetening properties similar to those associated with common sugar sweetening agents, yet are either not metabolized by the body or are metabolized only to a small extent. Thus, they are ideal sweetening agents for persons whose metabolizable carbohydrate intake must be restricted because of conditions such as diabetes mellitus or obesity. Moreover, because L-hexose sweetening agents provide little or no nutrient value for microorganisms, formulations prepared using L-hexoses as sweetening agents are less susceptible to spoilage.
The advantages of L-hexose monosaccharides, including L-gulose, as sweetening agents are set forth in U.S. Pat. No. 4,262,032, the disclosure of which is incorporated herein by reference.
A very desirable feature for an alternative sweetener is that it have bulk properties similar to sucrose or dextrose so that it can be substituted directly into standard formulations. L-Gulose has been known previously only as a syrupy liquid, or as an amorphous hygroscopic solid. Therefore, it would be desirable to have L-gulose in a crystalline, free flowing, non-hygroscopic form, that is, with physical properties similar to those of highly crystalline sweeteners such as sucrose and dextrose, so that it can be used in applications where a dry sweetener is required. Such applications include commercial dry, prepared mixes for making beverages, cakes, puddings, breads and the like and other food applications such as jams, jellies, icings, frostings and confections where the introduction of water into the formulation is undesirable.
A crystalline, free flowing, non-hygroscopic L-gulose, characterized by a high, sharp melting point, high initial specific optical rotation, mutarotation, characteristic X-ray powder diffraction and distinct infrared spectrum, has not been previously known. The Merck Index, Tenth Edition, 4459-4460 (1983) discloses that L-gulose is a syrup.
Many monosaccharides are known to exist in multiple crystalline forms which vary with respect to physical and chemical properties. For example, the common sugar D-glucose exists in two different isomeric forms, D-glucopyranose and .beta.-D-glucopyranose. ##STR1##
Both D-gulose isomers have been isolated in pure crystalline form. Although they do not differ in elementary composition, their physical and chemical properties differ as shown in the following table:
TABLE ______________________________________ PROPERTIES OF .alpha.-AND .beta.-D-GLUCOPYRANOSE PROPERTY .alpha.-D-glucopyranose .beta.-D-glucopyranose ______________________________________ Specific rotation +112.2.degree. +18.7.degree. Melting point, .degree.C. 146 150 Solubility in H.sub.2 O, 82.5 178 g per 100 mL Relative rate of oxida- 100 &lt;1.0 tion by glucose oxidase ______________________________________
Taste and sweetness level is also a function of the crystalline form of a sugar. For example, crystalline .beta.-D-mannopyranose is about half as sweet as glucose. On the other hand, crystalline .beta.-D-mannopyranose is distinctly bitter. Also, crystalline .beta.-D-fructopyranose tastes almost twice as sweet as sucrose while an aqueous solution of D-fructose, which exists as a mixture of several isomeric forms, is approximately equal to the sweetness of sucrose.
The novel crystalline L-gulose of this invention has been determined to consist entirely of the pure isomer .beta.-L-gulopyranose. In this crystalline form, .beta.-L-gulopyranose has been found to possess many desirable features which were not available from syrupy L-gulose. For example, it is free flowing, non-hygroscopic, highly pure and has a clean sweet taste. In this form, .beta.-L-gulopyranose is well-suited for applications where a dry, crystalline sweetener is required. Crystalline .beta.-L-gulopyranose is useful in other applications as well. For example, it can be used as an excipient, a chelating agent, a pharmaceutical intermediate, a cleaning agent for glass and metals, and as an additive for detergents.
In such applications, it is a very desirable feature to have a crystalline, free flowing form of L-gulose. For example, as an excipient, crystalline .beta.-L-gulopyranose may be combined with an active drug for preparing a convenient, agreeable dosage form, such as a tablet. As a pharmaceutical intermediate, crystalline .beta.-L-gulopyranose may be used in chemical processes where water is detrimental or where high purity is required to avoid formation of toxic by-products.
In the preparation of L-gulose by Dahlhoff, et al, Agnew. Chem., 92(7) 552-3 (1980), the final product obtained was a water free glassy solid which could be ground to a very hygroscopic white powder. The powder softened over a broad temperature range (60.degree.-80.degree. C.) to give a clear melt at 80.degree. C. Another solid was obtained by precipitating the L-gulose from ethanol with diethyl ether, but no melting range or other physical properties are given for this second product.
U.S. Pat. No. 4,371,616, Huibers, issued Feb. 1, 1983, describes a process for the production of several L-sugars, which process includes the separation and recovery of L-gulose by fractional crystallization. The disclosure contains no experimental data or physical properties of the L-gulose obtained by the method of the patent. The crystalline form of L-gulose of our invention is distinguished from the disclosure by Huibers in that the single, distinct isomer, .beta.-L-gulopyranose, having desirable, well-defined physical and chemical properties has been obtained.
Van Hook and Mac Innes, Sugar Journal, 16(5), 20(1953) describe the crystallization by sonic irradiation of several sugars including arabinose, fructose, sorbitol, gulose, and others. In this article no physical properties are given and it is not specified whether D-gulose or L-gulose was crystallized.